ABSTRACT HIV prevalence is above 30% among people who inject drugs (PWID) in Vietnam. There is an urgent need for prevention programs to slow ongoing transmission and provide treatment services for large populations of HIV- positive PWID. High levels of needle-sharing and limited uptake of antiretroviral therapy (ART) result in persistently high HIV incidence among PWID. Reducing risk behaviors and engaging this population in HIV care present significant challenges, and the high burden of depression among PWID may be at the root of those challenges. Up to 50% of PWID in Vietnam have been found to suffer from severe depressive symptoms, and a large body of research shows that comorbid depression consistently results in poorer HIV treatment outcomes. However, the role of depression in forward HIV transmission is still unclear. The proposed study hypothesizes that depression among PWID increases injecting and sexual risk behaviors and reduces engagement in HIV care and adherence to ART, resulting in uncontrolled HIV viral load. Through facilitating both risk behaviors and biological infectiousness, depression is hypothesized to result in increased forward transmission to susceptible partners. The proposed study is the first to simultaneously investigate the role of depression in forward spread of HIV infection through both behavioral and biological pathways and to use mathematical modeling to quantify the potential HIV prevention benefits of possible interventions in this key population. This study will use data collected from 336 newly diagnosed HIV-positive PWID in Thai Nguyen, Vietnam prior to HIV diagnosis and during the two years after diagnosis. Aims 1 and 2 of this study will estimate the association of depression with transmission risk behaviors (Aim 1) and HIV viral load (Aim 2), both before and after HIV diagnosis. Aim 3 will then develop a mathematical model of forward transmission among PWID in Vietnam to quantify the contribution of depression to new HIV infections. This model will be the first to estimate secondary transmission events among HIV-positive PWID in Vietnam and quantify HIV infections that could be averted using current prevention strategies (ART, needle exchanges, methadone maintenance programs) and potential future interventions (depression screening and treatment). The proposed study is an innovative approach, combining traditional epidemiologic methods with mathematical modeling to better understand the HIV epidemic and guide control efforts among PWID in Vietnam. This study focuses on an important consequence of drug abuse, HIV transmission, and aims to reduce this harm, which are research areas identified by NIDA as high priority. Depression screening and treatment may be critical to reducing risky behaviors, achieving viral suppression, and ultimately, slowing forward transmission in a key population that drives the HIV epidemic.